Selective Anesthesia-induced Neuroinflammation in Developing Mouse Brain and Cognitive Impairment

Article (PDF Available)inAnesthesiology 118(3) · January 2013with58 Reads
DOI: 10.1097/ALN.0b013e3182834d77 · Source: PubMed
Background: : Recent population studies have suggested that children with multiple exposures to anesthesia and surgery at an early age are at an increased risk of cognitive impairment. The authors therefore have established an animal model with single versus multiple exposures of anesthetic(s) in young versus adult mice, aiming to distinguish the role of different types of anesthesia in cognitive impairment. Methods: : Six- and 60-day-old mice were exposed to various anesthesia regimens. The authors then determined the effects of the anesthesia on learning and memory function, levels of proinflammatory cytokine interleukin-6 and tumor necrosis factor-α in brain tissues, and the amount of ionized calcium-binding adaptor molecule 1-positive cells, the marker of microglia activation, in the hippocampus. Results: : In this article, the authors show that anesthesia with 3% sevoflurane for 2 h daily for 3 days induced cognitive impairment and neuroinflammation (e.g., increased interleukin-6 levels, 151 ± 2.3% [mean ± SD] vs. 100 ± 9.0%, P = 0.035, n = 6) in young but not in adult mice. Anesthesia with 3% sevoflurane for 2 h daily for 1 day and 9% desflurane for 2 h daily for 3 days induced neither cognitive impairment nor neuroinflammation. Finally, an enriched environment and antiinflammatory treatment (ketorolac) ameliorated the sevoflurane-induced cognitive impairment. Conclusions: : Anesthesia-induced cognitive impairment may depend on developmental stage, anesthetic agent, and number of exposures. These findings also suggest the cellular basis and the potential prevention and treatment strategies for anesthesia-induced cognitive impairment, which may ultimately lead to safer anesthesia care and better postoperative outcomes for children.

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Available from: Yiying Zhang, Jun 12, 2015
    • "Since millions of children undergo general anesthesia worldwide each year, elucidation of the mechanisms underlying anesthetic-induced neurotoxicity in developing brain is not only of general scientific interest, but may also have substantial public health significance. Sevoflurane, a commonly used anesthetic in children, has been shown to induce apoptosis [4,5], neuroinflammation [6], Tau phosphorylation [7], as well as cognitive impairment [5][6][7][8] in young mice. Synapses mediate long-term memory in the brain; dendritic spines are the anatomical locus of most excitatory synapses in the central nervous system [9]. "
    [Show abstract] [Hide abstract] ABSTRACT: Early postnatal anesthesia causes long-lasting learning and memory impairment in rodents, however, evidence for a specific neurotoxic effect on early synaptogenesis has not been demonstrated. Drebrin A is an actin binding protein whose localization in dendritic protrusions serves an important role in dendritic spine morphogenesis, and is a marker for early synaptogenesis. We therefore set out to investigate whether clinically-relevant concentrations of anesthetic sevoflurane, widely- used in infants and children, alters dendritic morphology in cultured fetal day 16 mouse hippocampal neurons. After 7 days in vitro, mouse hippocampal neurons were exposed to four hours of 3% sevoflurane in 95% air/5% CO2 or control condition (95% air/5% CO2). Neurons were fixed in 4% paraformaldehyde and stained with Alexa Fluor555-Phalloidin, and/or rabbit anti-mouse drebrin A/E antibodies which permitted subcellular localization of filamentous (F)-actin and/or drebrin immunoreactivity, respectively. Sevoflurane caused acute significant length-shortening in filopodia and thin dendritic spines in days-in-vitro 7 neurons, an effect which was completely rescued by co-incubating neurons with ten micromolar concentrations of the selective Rho kinase inhibitor Y27632. Filopodia and thin spine recovered in length two days after sevoflurane exposure. Yet cluster-type filopodia (a precursor to synaptic filopodia) were persistently significantly decreased in number on day-in-vitro 9, in part owing to preferential localization of drebrin immunoreactivity to dendritic shafts versus filopodial stalks. These data suggest that sevoflurane induces F-actin depolymerization leading to acute, reversible length-shortening in dendritic protrusions through a mechanism involving (in part) activation of RhoA/Rho kinase signaling and impairs localization of drebrin A to filopodia required for early excitatory synapse formation.
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    • "Since the mitochondrial apoptotic pathway can be triggered intrinsically or with extrinsic pathway signals converging, we also examined the expression levels of Bcl-2 family members and cas- pase-9 after propofol anesthesia. As Fas/FasL system has been known to act as a mediator of inflammation in CNS pathology (Choi and Benveniste 2004) and as most recent studies point to the importance of inflammation in anesthetic toxicity, caspase-1, interleukine-1b (IL-1b) and activation of microglia (Cao et al. 2012; Tanaka et al. 2013; Ye et al. 2013; Shen et al. 2013), the focus of our study aims to determine if propofol anesthesia could interconnect pro-apoptotic and pro-inflammatory signaling in the developing brain. We also studied the cognitive processes that include attention and motor activity later in life (P35, P60) to assess long-term consequences of the propofol treatment. "
    [Show abstract] [Hide abstract] ABSTRACT: A number of experimental studies have reported that exposure to common, clinically used anesthetics induce extensive neuroapoptosis and cognitive impairment when applied to young rodents, up to 2 weeks old, in phase of rapid synaptogenesis. Propofol is the most used general anesthetic in clinical practice whose mechanisms of neurotoxicity on the developing brain remains to be examined in depth. This study investigated effects of different exposures to propofol anesthesia on Fas receptor and Fas ligand expressions, which mediate proapoptotic and proinflammation signaling in the brain. Propofol (20 mg/kg) was administered to 7-day-old rats in multiple doses sufficient to maintain 2-, 4- and 6-h duration of anesthesia. Animals were sacrificed at 0, 4, 16 and 24 h after termination of anesthesia. It was found that propofol anesthesia induced Fas/FasL and downstream caspase-8 expression more prominently in the thalamus than in the cortex. Opposite, Bcl-2 and caspase-9, markers of intrinsic pathway activation, were shown to be more influenced by propofol treatment in the cortex. Further, we have established upregulation of caspase-1 and IL-1β cytokine transcription as well as subsequent activation of microglia that is potentially associated with brain inflammation. Behavioral analyses revealed that P35 and P60 animals, neonatally exposed to propofol, had significantly higher motor activity during three consecutive days of testing in the open field, though formation of the intersession habituation was not prevented. This data, together with our previous results, contributes to elucidation of complex mechanisms of propofol toxicity in developing brain.
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    • "water maze (MWM) test was performed as described previously with some mod- ifications [5]. Briefly, the P31 mice were trained in a round water-filled steel tank that contained a hidden 10 cm diameter platform. "
    [Show abstract] [Hide abstract] ABSTRACT: Sevoflurane exposures were demonstrated to induce neurotoxicity in the developing brain in both human and animal studies. However, there is no effective approach to reverse it. The present study aimed to evaluate the feasibility of utilizing docosahexaenoic acid (DHA) to prevent sevoflurane-induced neurotoxicity. P6 (postnatal 6 days) mice were administrated DHA after exposure to 3% sevoflurane for two hours daily in three consecutive days. Molecular expressions of synaptic makers (PSD95, synaptophysin) and synaptic morphological changes were investigated by Western blot analysis and transmission electron microscopy, respectively. Meanwhile, Morris water maze test was used to assess spatial memory of mice at P31 (postnatal 31 days). DHA restored sevoflurane-induced decreased level of PSD95 and synaptophysin expressions and increased PSD areas and also improved long-term spatial memory. These results suggest that DHA could rescue synaptogenesis impairment and long-term memory deficits in postnatal caused by multiple sevoflurane exposures.
    Full-text · Article · Jan 2016
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